The EconomistMarch 14th 2020 BriefingThe covid-19 virus 152
1shoe bat to a person (possibly by way of
some intermediary). The subsequent out-
break went on to kill almost 800 people
around the world.
Some of the studies which followed that
outbreak highlighted the fact that related
coronaviruses could easily follow sars-
covacross the species barrier into humans.
Unfortunately, this risk did not lead to the
development of specific drugs aimed at
such viruses. When sars-cov-2—similarly
named because of its very similar ge-
nome—duly arrived, there were no dedi-
cated anti-coronavirus drugs around to
meet it.As a known enemy
A sars-cov-2virus particle, known techni-
cally as a virion, is about 90 nanometres
(billionths of a metre) across—around a
millionth the volume of the sort of cells it
infects in the human lung. It contains four
different proteins and a strand of rna—a
molecule which, like dna, can store genet-
ic information as a sequence of chemical
letters called nucleotides. In this case, that
information includes how to make all the
other proteins that the virus needs in order
to make copies of itself, but which it does
not carry along from cell to cell.
The outer proteins sit athwart a mem-
brane provided by the cell in which the viri-
on was created. This membrane, made of
lipids, breaks up when it encounters soap
and water, which is why hand-washing is
such a valuable barrier to infection.
The most prominent protein, the one
which gives the virions their crown- or
mine-like appearance by standing proud of
the membrane, is called spike. Two other
proteins, envelope protein and membrane
protein, sit in the membrane between
these spikes, providing structural integri-
ty. Inside the membrane a fourth protein,
nucleocapsid, acts as a scaffold around
which the virus wraps the 29,900 nucleo-
tides of rnawhich make up its genome.
Though they store their genes in dna,
living cells use rnafor a range of other ac-
tivities, such as taking the instructions
written in the cell’s genome to the machin-
ery which turns those instructions into
proteins. Various sorts of virus, though,
store their genes on rna. Viruses like hiv,
which causes aids, make dnacopies of
their rnagenome once they get into a cell.
This allows them to get into the nucleus
and stay around for years. Coronaviruses
take a simpler approach. Their rnais for-
matted to look like the messenger rna
which tells cells what proteins to make. As
soon as that rnagets into the cell, flum-
moxed protein-making machinery starts
reading the viral genes and making the pro-
teins they describe.
First contact between a virion and a cell
is made by the spike protein. There is a re-
gion on this protein that fits hand-in-glovewith ace2, a protein found on the surface
of some human cells, particularly those in
the respiratory tract.
ace2 has a role in controlling blood
pressure, and preliminary data from a hos-
pital in Wuhan suggest that high blood
pressure increases the risks of someone
who has contracted the illness dying of it
(so do diabetes and heart disease). Whether
this has anything to do with the fact that
the virus’s entry point is linked to blood-
pressure regulation remains to be seen.
Once a virion has attached itself to an
ace2molecule, it bends a second protein
on the exterior of the cell to its will. This is
tmprss2, a protease. Proteases exist to
cleave other proteins asunder, and the vi-
rus depends on tmprss2obligingly cutting
open the spike protein, exposing a stump
called a fusion peptide. This lets the virion
into the cell, where it is soon able to open
up and release its rna(see diagram).
Coronaviruses have genomes bigger
than those seen in any other rna viruses—
about three times longer than hiv’s, twice
as long as the influenza virus’s, and half as
long again as the Ebola virus’s. At one end
are the genes for the four structural pro-
teins and eight genes for small “accessory”
proteins that seem to inhibit the host’s de-
fences (see diagram on next page). Togeth-
er these account for just a third of the ge-
nome. The rest is the province of a complex
gene called replicase. Cells have no interest
in making rnacopies of rnamolecules,
and so they have no machinery for the task
that the virus can hijack. This means the vi-
rus has to bring the genes with which to
make its own. The replicase gene creates
two big “polyproteins” that cut themselves
up into 15, or just possibly 16, short “non-
structural proteins” (nsps). These make up
the machinery for copying and proofread-
ing the genome—though some of them
may have other roles, too.
Once the cell is making both structural
proteins and rna, it is time to start churn-
ing out new virions. Some of the rnamole-
cules get wrapped up with copies of the nu-
cleocapsid proteins. They are thenprovided with bits of membrane which are
rich in the three outer proteins. The enve-
lope and membrane proteins play a large
role in this assembly process, which takes
place in a cellular workshop called the Gol-
gi apparatus. A cell may make between 100
and 1,000 virions in this way, according to
Stanley Perlman of the University of Iowa.
Most of them are capable of taking over a
new cell—either nearby or in another
body—and starting the process off again.
Not all the rnathat has been created
ends up packed into virions; leftovers es-
cape into wider circulation. The coronavi-
rus tests now in use pick up and amplify
sars-cov-2-specific rnasequences found
in the sputum of infected patients.Take your time, hurry up
Because a viral genome has no room for
free riders, it is a fair bet that all of the pro-
teins that sars-cov-2makes when it gets
into a cell are of vital importance. That
makes each of them a potential target for
drug designers. In the grip of a pandemic,
though, the emphasis is on the targets that
might be hit by drugs already at hand.
The obvious target is the replicase sys-
tem. Because uninfected cells do not make
rnacopies of rnamolecules, drugs which
mess that process up can be lethal to the vi-
rus while not necessarily interfering with
the normal functioning of the body. Simi-
lar thinking led to the first generation of
anti-hiv drugs, which targeted the process
that the virus uses to transcribe its rnage-
nome into dna—another thing that
healthy cells just do not do.
Like those first hiv drugs, some of the
most promising sars-cov-2 treatments are
molecules known as “nucleotide ana-
logues”. They look like the letters of which
rnaor dnasequences are made up; but
when a virus tries to use them for that pur-
pose they mess things up in various ways.
The nucleotide-analogue drug that has
gained the most attention for fighting
sars-cov-2 is remdesivir. It was originally
developed by Gilead Sciences, an American
biotechnology firm, for use against EbolaHijackSources:Songetal.,Viruses,2019;Jiangetal.,EmergingMicrobesandInfections,2012;TheEconomistHowSARS-CoV-2replicatesitselfinthecellsofthoseinfectedCellme
mbran
eTMPRSSGolgi
Protein-making
machinerySARS-CoV-NewSARS-
CoV-↑
↑↗↑↑→ →→↘↘ Replicationcomplex1234
5 6
RNA
ViralproteinsACE1 Spike protein on the virion binds to ACE2, a cell-surface protein. TMPRSS2, an enzyme, helps the virion enter 2 The
virion releases its RNA 3 Some RNA is translated into proteins by the cell's machinery 4 Some of these proteins form a
replication complex to make more RNA 5 Proteins and RNA are assembled into a new virion in the Golgi and 6 released